We hypothesize that poor sleep increases the likelihood of transitioning from acute to chronic pain. Specifically, we propose that disrupted or insufficient sleep alters the nociceptive system, making it more susceptible to maladaptive plasticity after peripheral nerve injury, resulting in chronic pain. Conversely, we hypothesize tha promoting restorative sleep will reduce the risk of developing persistent neuropathic pain. To test these hypotheses, we propose three aims: In Aim 1, we will test if moderate, chronic sleep disturbance increases acute nociceptive pain sensitivity. We will reduce or fragment sleep in mice for periods up to several weeks and measure pain sensitivity before, during and after the sleep disruption. In Aim 2, we will examine how sleep disruption contributes to the development of chronic pain. We will focus on pain-related outcomes such as cold allodynia and pinprick hyperalgesia because their development is variable in C57BL/6j mice after standard forms of peripheral nerve injury. We will produce chronic sleep disruption (partial sleep deprivation or sleep fragmentation) before peripheral nerve injury, and we will then measure the onset, intensity and duration of pain related behavior. We anticipate that sleep disruption will increase neuropathic pain behavior. To determine if sleep disruption affects CNS synaptic plasticity, we will also measure secondary hyperalgesia caused by intraplantar injection of capsaicin as a model of central sensitization, and we will then quantify the number of c-fos and p-ERK positive neurons in the superficial dorsal horn. In Aim 3, we will pharmacologically promote sleep immediately after nerve injury and for several days to determine whether enhancing sleep in mice reduces the risk of developing chronic pain. To examine the roles of distinct neurochemical systems, we will administer three classes of hypnotic drugs that act on different systems (benzodiazepines, orexin antagonists, and gamma hydroxybutyrate). We expect that increasing the amount of sleep and reducing sleep fragmentation will reduce the risk of developing chronic pain. These multidisciplinary experiments have substantial scientific and clinical implications as they should shed light on how poor quality sleep promotes the transition from acute pain to maladaptive, chronic pain, and how improved sleep can reduce pain. PUBLIC HEALTH RELEVANCE: Patients often report that poor sleep worsens their pain. We will examine how insufficient sleep and fragmented sleep contribute to the development of chronic pain after peripheral nerve injury in mice. Understanding how poor sleep affects the development of chronic pain should lead to better strategies for preventing and treating chronic pain.